title: Ozone induces glucose intolerance and systemic metabolic effects in young and aged Brown Norway rats.
abstract: Air pollutants have been associated with increased diabetes in humans. We hypothesized that ozone would impair glucose homeostasis by altering insulin signaling and/or endoplasmic reticular (ER) stress in young and aged rats. One, 4, 12, and 24 month old Brown Norway (BN) rats were exposed to air or ozone, 0.25 or 1.0 ppm, 6 h/day for 2 days (acute) or 2 d/week for 13 weeks (subchronic). Additionally, 4 month old rats were exposed to air or 1.0 ppm ozone, 6 h/day for 1 or 2 days (time-course). Glucose tolerance tests (GTT) were performed immediately after exposure. Serum and tissue biomarkers were analyzed 18 h after final ozone for acute and subchronic studies, and immediately after each day of exposure in the time-course study. Age-related glucose intolerance and increases in metabolic biomarkers were apparent at baseline. Acute ozone caused hyperglycemia and glucose intolerance in rats of all ages. Ozone-induced glucose intolerance was reduced in rats exposed for 13 weeks. Acute, but not subchronic ozone increased α2-macroglobulin, adiponectin and osteopontin. Time-course analysis indicated glucose intolerance at days 1 and 2 (2>1), and a recovery 18 h post ozone. Leptin increased day 1 and epinephrine at all times after ozone. Ozone tended to decrease phosphorylated insulin receptor substrate-1 in liver and adipose tissues. ER stress appeared to be the consequence of ozone induced acute metabolic impairment since transcriptional markers of ER stress increased only after 2 days of ozone. In conclusion, acute ozone exposure induces marked systemic metabolic impairments in BN rats of all ages, likely through sympathetic stimulation.
authors.affiliation: Environmental Public Health Division, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC, USA.
authors.forename: V
authors.initials: V
authors.lastname: Bass
authors.forename: C J
authors.initials: CJ
authors.lastname: Gordon
authors.forename: K A
authors.initials: KA
authors.lastname: Jarema
authors.forename: R C
authors.initials: RC
authors.lastname: MacPhail
authors.forename: W E
authors.initials: WE
authors.lastname: Cascio
authors.forename: P M
authors.initials: PM
authors.lastname: Phillips
authors.forename: A D
authors.initials: AD
authors.lastname: Ledbetter
authors.forename: M C
authors.initials: MC
authors.lastname: Schladweiler
authors.forename: D
authors.initials: D
authors.lastname: Andrews
authors.forename: D
authors.initials: D
authors.lastname: Miller
authors.forename: D L
authors.initials: DL
authors.lastname: Doerfler
authors.forename: U P
authors.initials: UP
authors.lastname: Kodavanti
mesh_terms: D052242:Adiponectin / Q000097:blood; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000367:Age Factors; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D003920:Diabetes Mellitus / Q000139:chemically induced / Q000473:pathology; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D018149:Glucose Intolerance / Q000139:chemically induced / Q000473:pathology*; D005951:Glucose Tolerance Test; D007328:Insulin / Q000097:blood; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000378:metabolism; D007333:Insulin Resistance; D020738:Leptin / Q000097:blood; D008075:Lipoproteins, HDL / Q000097:blood; D053419:Lipoproteins, IDL / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008659:Metabolic Diseases / Q000139:chemically induced / Q000473:pathology*; D053495:Osteopontin / Q000097:blood; D010126:Ozone / Q000633:toxicity*; D010766:Phosphorylation; D051381:Rats; D011914:Rats, Inbred BN; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012307:Risk Factors; D014280:Triglycerides / Q000097:blood; D000511:alpha-Macroglobulins / Q000378:metabolism
chemical_list: D052242:Adiponectin; D015415:Biomarkers; C526292:IRS1 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D020738:Leptin; D008075:Lipoproteins, HDL; D053419:Lipoproteins, IDL; D014280:Triglycerides; D000511:alpha-Macroglobulins; D053495:Osteopontin; D010126:Ozone
keywords: Aging; Air pollution; Epinephrine; Metabolic syndrome; Ozone; Serum biomarkers